Inhibition of glycine transporter-1 reduces cue-induced nicotine-seeking, but does not promote extinction of conditioned nicotine cue responding in the rat
Inhibition of glycine transporter-1 reduces cue-induced nicotine-seeking, but does not promote extinction of conditioned nicotine cue responding in the rat
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DOI：
10.1111/adb.12049
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发表时间：
2013-09-01
影响因子：
3.4
通讯作者：
Bifone, Angelo
中科院分区：
文献类型：
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作者：
Cervo, Luigi;Di Clemente, Angelo;Bifone, Angelo
药物刺激N-甲基-D-天冬氨酸受体（NMDAr）可以增强戒烟线索暴露疗法的效果。NMDAr刺激可以通过增加突触甘氨酸水平来实现，甘氨酸是一种必需的共激动剂。在这里，我们评估了SSR 504734（一种甘氨酸I型转运蛋白（GlyT 1）的选择性抑制剂）在灭绝恢复过程中诱导大鼠稳健且持久的尼古丁寻求行为的影响。在双层操作笼中，雄性Wistar大鼠被训练将辨别性刺激（S（D）s）与尼古丁（0.03 mg/kg/65 L/2秒/输注）或蔗糖（45 mg颗粒）的可用性相关联，而非奖励。强化反应之后是提示信号20秒暂停（CS）。一旦满足训练标准，大鼠在不存在刺激物、S（D）s和CS的情况下经历杠杆按压的消退。再次暴露于尼古丁或蔗糖SD+/CS+，而不是非奖励SD-/CS-，恢复了先前加强的水平。用SSR 504734（10 mg/kg i. p.）急性预处理减少尼古丁寻求行为，但不影响大鼠的运动活性。每日暴露于SD+/CS+期间的亚慢性给药（10 mg/kg i. p.，持续5天）减少了尼古丁觅药;然而，该效应是一过性的，在72小时时恢复至SD+/CS+应答。1个月后观察到SD+/CS+反应完全恢复，表明SSR 504734亚急性给药未涉及可能与尼古丁寻求相关的长期可塑性机制。总之，GlyT 1抑制剂可能为急性线索控制的尼古丁寻求提供治疗机会，但缺乏与尼古丁线索暴露相关的亚慢性治疗的持续作用表明，短期给予GlyT 1抑制剂SSR 504734不足以促进尼古丁线索条件反应的消退。
Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (S(D)s) with the availability of nicotine (0.03mg/kg/65L/2second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, S(D)s and CSs. Re-exposure to nicotine or sucrose SD+/CS+, but not non-reward SD-/CS-, revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10mg/kg i.p. for 5 days) during daily exposure to SD+/CS+ reduced nicotine-seeking; however, this effect was transient, with return to SD+/CS+ responding at 72 hours. Full recovery to SD+/CS+ responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding.